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Injectable Amoxicillin Versus Injectable Ampicillin Plus Gentamicin in the Treatment of Severe Pneumonia in Children Aged 2 to 59 Months: Protocol for an Open-Label Randomized Controlled Trial.

ABSTRACT: BACKGROUND:Pneumonia causes about 0.9 million deaths worldwide each year. The World Health Organization (WHO) guidelines for the standard management of severe pneumonia requires parenteral ampicillin every 6 hours and once-daily parenteral gentamicin for 5 to 7 days. Although this treatment has contributed to the reduction of mortality, it requires nursing interventions every 6 hours for 7 days. Further intervention trials should be conducted to search for alternate antibiotics with better adherence, reduced cost, and reduced hospital stay. Parenteral amoxicillin is an effective alternative to ampicillin, as it has a longer half-life and broader coverage. OBJECTIVE:The aim of this clinical trial is to compare the efficacy of a dose of injectable amoxicillin every 12 hours plus a once-daily dose of injectable gentamicin with a dose of injectable ampicillin every 6 hours plus a once-daily dose of injectable gentamicin in children hospitalized for severe pneumonia. METHODS:This randomized, controlled, open-label, noninferiority trial is being conducted in Dhaka Hospital of the International Centre for Diarrheal Disease Research, Bangladesh. A sample size of 308 children with severe pneumonia will give adequate power to this study. Children aged 2 to 59 months are randomized to either intravenous ampicillin or intravenous amoxicillin, plus intravenous gentamicin in both study arms. The monitoring of the patients is carried out according to the WHO protocol for the treatment of severe pneumonia. The primary objective is the rate of treatment failure, defined by the persistence of danger signs of severe pneumonia beyond 48 hours or deterioration within 24 hours of initiation of the therapy. The secondary objectives are (1) improvement in or the resolution of danger signs since enrollment, (2) length of hospital stay, (3) death during hospitalization, and (4) rate of nosocomial infections. RESULTS:Enrollment in the study started on January 1, 2018, and ended on October 31, 2019. Data entry and analysis are in progress. Findings from the study are expected to be disseminated in October 2020. CONCLUSIONS:Our study's findings will improve compliance with the use of antibiotics that require less frequent doses for the treatment of severe pneumonia. TRIAL REGISTRATION:ClinicalTrials.gov NCT03369093; https://clinicaltrials.gov/ct2/show/NCT03369093. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/17735.

SUBMITTER: Shahrin L

PROVIDER: S-EPMC7669443 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Injectable Amoxicillin Versus Injectable Ampicillin Plus Gentamicin in the Treatment of Severe Pneumonia in Children Aged 2 to 59 Months: Protocol for an Open-Label Randomized Controlled Trial.

Shahrin Lubaba L Chisti Mohammod Jobayer MJ Shahid Abu Sadat Mohammad Sayeem Bin ASMSB Rahman Abu Sayem Mirza Mohammad Hasibur ASMMH Islam Md Zahidul MZ Afroze Farzana F Huq Sayeeda S Ahmed Tahmeed T

JMIR research protocols 20201102 11

<h4>Background</h4>Pneumonia causes about 0.9 million deaths worldwide each year. The World Health Organization (WHO) guidelines for the standard management of severe pneumonia requires parenteral ampicillin every 6 hours and once-daily parenteral gentamicin for 5 to 7 days. Although this treatment has contributed to the reduction of mortality, it requires nursing interventions every 6 hours for 7 days. Further intervention trials should be conducted to search for alternate antibiotics with bett ...[more]

PMID: 33136058

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Project description:The World Health Organization (WHO) recommends intravenous (IV) ampicillin and gentamicin as first-line therapy to treat severe pneumonia in children under five years of age. Ampicillin needs to be administered at a six-hourly interval, which requires frequent nursing intervention and bed occupancy for 5-7 days, limiting its utility in resource-poor settings. We compared the efficacy of IV amoxicillin over IV ampicillin, which is a potential alternative drug in treating severe pneumonia in children between 2-59 months. We conducted an unblinded, randomized, controlled, non-inferiority trial in the Dhaka hospital of icddr,b from 1 January 2018 to 31 October 2019. Children from 2-59 months of age presenting with WHO defined severe pneumonia with respiratory danger signs were randomly assigned 1:1 to either 50 mg/kg ampicillin or 40 mg/kg amoxicillin per day with 7.5 mg/kg gentamicin. The primary outcome was treatment failure as per the standard definition of persistence of danger sign(s) of severe pneumonia beyond 48 h or deterioration within 24 h of therapy initiation. The secondary outcomes were: (i) time required for resolution of danger signs since enrolment, (ii) length of hospital stay, (iii) death during hospitalization, and (iv) rate of nosocomial infections. Among 308 enrolled participants, baseline characteristics were similar among the two groups. Sixty-two (20%) children ended up with treatment failure, 21 (14%) in amoxicillin, and 41 (27%) in ampicillin arm, which is statistically significant (relative risk [RR] 0.51, 95% CI 0.32-0.82; p = 0.004). We reported 14 deaths for serious adverse events, 4 (3%) and 10 (6%) among amoxicillin and ampicillin arm, respectively. IV amoxicillin and IV gentamicin combination is not inferior to combined IV ampicillin and IV gentamicin in treating severe pneumonia in under-five children in Bangladesh. Considering the less frequent dosing and more compliance, IV amoxicillin is a better choice for treating children with severe pneumonia in resource-limited settings.

Project description:BackgroundFirst dose oral co-trimoxazole and referral are recommended for WHO-defined severe pneumonia. Difficulties with referral compliance are reported in many low-resource settings, resulting in low access to appropriate treatment. The objective in this study was to assess whether community case management by lady health workers (LHWs) with oral amoxicillin in children with severe pneumonia was equivalent to current standard of care.MethodsIn Haripur district, Pakistan, 28 clusters were randomly assigned with stratification in a 1:1 ratio to intervention and control clusters by use of a computer-generated randomisation sequence. Children were included in the study if they were aged 2-59 months with WHO-defined severe pneumonia and living in the study area. In the intervention clusters, community-based LHWs provided mothers with oral amoxicillin (80-90 mg/kg per day or 375 mg twice a day for infants aged 2-11 months and 625 mg twice a day for those aged 12-59 months) with specific guidance on its use. In control clusters, LHWs gave the first dose of oral co-trimoxazole (age 2-11 months, sulfamethoxazole 200 mg plus trimethoprim 40 mg; age 12 months to 5 years, sulfamethoxazole 300 mg plus trimethoprim 60 mg) and referred the children to a health facility for standard of care. Participants, carers, and assessors were not masked to treatment assignment. The primary outcome was treatment failure by day 6. Analysis was per protocol with adjustment for clustering within groups by use of generalised estimating equations. This study is registered, number ISRCTN10618300.FindingsWe assigned 1995 children to treatment in 14 intervention clusters and 1477 in 14 control clusters, and we analysed 1857 and 1354 children, respectively. Cluster-adjusted treatment failure rates by day 6 were significantly reduced in the intervention clusters (165 [9%] vs 241 [18%], risk difference -8·9%, 95% CI -12·4 to -5·4). Further adjustment for baseline covariates made little difference (-7·3%, -10·1 to -4·5). Two deaths were reported in the control clusters and one in the intervention cluster. Most of the risk reduction was in the occurrence of fever and lower chest indrawing on day 3 (-6·7%, -10·0 to -3·3). Adverse events were diarrhoea (n=4) and skin rash (n=1) in the intervention clusters and diarrhoea (n=3) in the control clusters.InterpretationCommunity case management could result in a standardised treatment for children with severe pneumonia, reduce delay in treatment initiation, and reduce the costs for families and health-care systems.FundingUnited States Agency for International Development (USAID).

Project description:ImportancePneumonia is the leading infectious killer of children. Rigorous evidence supporting antibiotic treatment of children with nonsevere fast-breathing pneumonia in low-resource African settings is lacking.ObjectiveTo assess whether treatment with placebo for nonsevere fast-breathing pneumonia is substantively less effective than 3 days of treatment with amoxicillin.Design, setting, and participantsThis double-blind, 2-arm, randomized clinical noninferiority trial with follow-up of 14 days screened 1343 HIV-uninfected children aged 2 to 59 months with nonsevere fast-breathing pneumonia at outpatient departments of hospitals in Lilongwe, Malawi, Africa, between June 2016 and June 2017.InterventionsPlacebo or amoxicillin dispersible tablets administered twice daily for 3 days.Main outcomes and measuresThe primary end point was the proportion of children failing treatment by day 4 with a relative noninferiority margin of 1.5 times the failure rate in the amoxicillin group. Primary analyses were performed based on the intention-to-treat principle. Planned secondary analyses included treatment failure or relapse by day 14.ResultsIn total, 1126 children were randomized to 3 days of amoxicillin (n = 564) or placebo (n = 562) therapy. Baseline demographic and clinical characteristics were similar between the groups. For the entire study population, the mean (SD) age was 21.3 (15.1) months, and 601 (53.4%) were female. After an interim analysis, the data safety monitoring board stopped the study because children receiving amoxicillin had a 4.0% (22 of 552 with outcome data) treatment failure rate by day 4, whereas children receiving placebo had a 7.0% (38 of 543) treatment failure rate (adjusted relative risk, 1.78; 95% CI, 1.07%-2.97%; adjusted absolute difference, 3.0%; 95% CI, 0.4%-5.7%). Among children with known day 14 outcomes, 56 of 552 (10.1%) receiving amoxicillin and 64 of 543 (11.8%) receiving placebo had either treatment failure by day 4 or relapse by day 14 (relative risk, 1.16; 95% CI, 0.83%-1.63%; absolute difference, 1.6%; 95% CI, -2.1% to 5.4%). There were no deaths.Conclusions and relevanceIn HIV-uninfected children aged 2 to 59 months in a malaria-endemic region of Malawi, placebo treatment of nonsevere fast-breathing pneumonia was significantly inferior to treatment with amoxicillin. However, by day 4, approximately 93% of children receiving placebo were without treatment failure, and there was no significant difference between groups in treatment failure or relapse by day 14. The number of children with nonsevere fast-breathing pneumonia that needed amoxicillin treatment for 1 child to benefit was 33.Trial registrationClinicalTrials.gov Identifier: NCT02760420.

Project description:BackgroundPneumonia is a leading cause of morbidity and mortality in children younger than five years of age. Most deaths occur during infancy and in low-income countries. Daily zinc supplements have been reported to prevent acute lower respiratory tract infection (LRTI) and reduce child mortality. This is an update of a review first published in 2010.ObjectivesTo evaluate the effectiveness of zinc supplementation in the prevention of pneumonia in children aged two to 59 months.Search methodsWe searched CENTRAL (Issue 21 October 2016), MEDLINE (1966 to October 2016), Embase (1974 to October 2016), LILACS (1982 to October 2016), CINAHL (1981 to October 2016), Web of Science (1985 to October 2016) and IMSEAR (1980 to October 2016).Selection criteriaRandomised controlled trials (RCTs) evaluating zinc supplementation for the prevention of pneumonia in children aged from 2 months to 59 months.Data collection and analysisTwo review authors independently assessed trial quality and extracted data.Main resultsWe did not identify any new studies for inclusion in this update. We included six studies that involved 5193 participants.Analysis showed that zinc supplementation reduced the incidence of pneumonia by 13% (fixed-effect risk ratio (RR) 0.87; 95% confidence interval (CI) 0.81 to 0.94, six studies, low-quality evidence) and prevalence of pneumonia by 41% (random-effects RR 0.59; 95% CI 0.35 to 0.99, one study, n = 609, low-quality evidence). On subgroup analysis, we found that zinc reduced the incidence of pneumonia defined by specific clinical criteria by 21% (i.e. confirmation by chest examination or chest radiograph) (fixed-effect RR 0.79; 95% CI 0.0.71 to 0.88, four studies, n = 3261), but had no effect on lower specificity pneumonia case definition (i.e. age-specific fast breathing with or without lower chest indrawing) (fixed-effect RR 0.95; 95% CI 0.86 to 1.06, four studies, n = 1932).Authors' conclusionsZinc supplementation in children is associated with a reduction in the incidence and prevalence of pneumonia.

Project description:Pneumonia is the leading cause of child mortality under five years of age worldwide. For pneumonia with chest indrawing in children aged 3-59 months, injectable penicillin and hospitalization was the recommended treatment. This increased the health care cost and exposure to nosocomial infections. We compared the clinical and cost outcomes of a seven day treatment with oral amoxicillin with the first 48 h of treatment given in the hospital (hospital group) or at home (home group).We conducted an open-label, multi-center, two-arm randomized clinical trial at six tertiary hospitals in India. Children aged 3 to 59 months with chest indrawing pneumonia were randomized to home or hospital group. Clinical outcomes, treatment adherence, and patient safety were monitored through home visits on day 3, 5, 8, and 14 with an additional visit for the home group at 24 h. Clinical outcomes included treatment failure rates up to 7 days (primary outcome) and between 8-14 days (secondary outcome) using the intention to treat and per protocol analyses. Cost outcomes included direct medical, direct non-medical and indirect costs for a random 17% subsample using the micro-costing technique.1118 children were enrolled and randomized to home (n = 554) or hospital group (n = 564). Both groups had similar baseline characteristics. Overall treatment failure rate was 11.5% (per protocol analysis). The hospital group was significantly more likely to fail treatment than the home group in the intention to treat analysis. Predictors with increased risk of treatment failure at any time were age 3-11 months, receiving antibiotics within 48 h prior to enrolment and use of high polluting fuel. Death rates at 7 or 14 days did not differ significantly. (Difference -0.0%; 95% CI -0.5 to 0.5). The median total treatment cost was Rs. 399 for the home group versus Rs. 602 for the hospital group (p < 0.001), for the same effect of 5% failure rate at the end of 7 days of treatment in the random subsample.Home based oral amoxicillin treatment was equivalent to hospital treatment for first 48 h in selected children of chest indrawing pneumonia and was cheaper. Consistent with the recent WHO simplified guidelines, management with home based oral amoxicillin for select children with only fast breathing and chest-indrawing can be a cost effective intervention.ClinicalTrials.gov NCT01386840, registered 25th June 2011 and the Indian Council of Medical Research REFCTRI/2010/000629.

Dataset Information

Injectable Amoxicillin Versus Injectable Ampicillin Plus Gentamicin in the Treatment of Severe Pneumonia in Children Aged 2 to 59 Months: Protocol for an Open-Label Randomized Controlled Trial.

Publications

Injectable Amoxicillin Versus Injectable Ampicillin Plus Gentamicin in the Treatment of Severe Pneumonia in Children Aged 2 to 59 Months: Protocol for an Open-Label Randomized Controlled Trial.

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